Abstract

Objective: Midbrain dopamine transmission is thought to regulate responses to rewarding drugs and drug-paired stimuli; however, the exact contribution, particularly in humans, remains unclear. In the present study, we tested whether decreasing dopamine synthesis, as produced by acute phenylalanine/tyrosine depletion (APTD), would alter responses to the stimulant drug, d-amphetamine.Methods: On 3 separate days, 14 healthy men received d-amphetamine (0.3 mg/kg, given orally) plus a nutritionally balanced amino acid mixture, the phenylalanine/tyrosine-deficient mixture or the phenylalanine/tyrosine-deficient mixture followed by the immediate dopamine precursor, L-DOPA (Sinemet, 2 × 100 mg/25 mg). Responses to these treatments were assessed with visual analog scales, the Profile of Mood States, and a computerized Go/No-Go task.Results: d-Amphetamine elicited its prototypical subjective effects, but these were not altered by APTD. In comparison, APTD significantly increased commission errors on the Go/No-Go task and did so uniquely in conditions where subjects were rewarded for making correct responses; this effect of APTD was prevented by L-DOPA.Conclusions: Together these results support the hypothesis that, in healthy men, dopamine is not closely linked to euphorogenic effects of abused substances but does affect the salience of reward-related cues and the ability to respond to them preferentially.

Acknowledgements: This work was supported by an operating grant from the Canadian Institutes of Health Research to M.L. (MOP–36429) and C.B; M.L. and C.B. are both recipients of salary awards from Fonds de la recherche en santé du Québec (FRSQ) and funded research chairs from McGill University. G.B.B. is a Canada Research Chair. M.a.h.R. received a scholarship from the Netherlands Brain Foundation. L.B. received a fellowship from the Netherlands Organisation for Scientific Research (NWO). We thank Franceen Lenoff and Gail Rauw for their excellent technical assistance.

Contributors: Drs. Leyton and Young designed the study. Dr. Leyton, Ms. aan het Rot and Drs. Baker and Benkelfat acquired the data, which Drs. Leyton, Booij, Baker and Benkelfat analyzed. All authors gave approval for the final version of the article to be published. Drs. Leyton and Booij wrote the article, and Ms. aan het Rot and Drs. Booij, Baker, Young and Benkelfat critically reviewed it.